NM_001048174.2(MUTYH):c.452A>G (p.Tyr151Cys) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Feb 16, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000115766.31

Allele description [Variation Report for NM_001048174.2(MUTYH):c.452A>G (p.Tyr151Cys)]

NM_001048174.2(MUTYH):c.452A>G (p.Tyr151Cys)

Gene:

MUTYH:mutY DNA glycosylase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p34.1

Genomic location:

Preferred name:

NM_001048174.2(MUTYH):c.452A>G (p.Tyr151Cys)

Other names:

p.Y165C:TAC>TGC

HGVS:

NC_000001.11:g.45332803T>C
NG_008189.1:g.12668A>G
NM_001048171.2:c.452A>G
NM_001048172.2:c.455A>G
NM_001048173.2:c.452A>G
NM_001048174.2:c.452A>GMANE SELECT
NM_001128425.2:c.536A>G
NM_001293190.2:c.497A>G
NM_001293191.2:c.485A>G
NM_001293192.2:c.176A>G
NM_001293195.2:c.452A>G
NM_001293196.2:c.176A>G
NM_001350650.2:c.107A>G
NM_001350651.2:c.107A>G
NM_012222.3:c.527A>G
NP_001041636.1:p.Tyr165Cys
NP_001041636.2:p.Tyr151Cys
NP_001041637.1:p.Tyr152Cys
NP_001041638.1:p.Tyr151Cys
NP_001041639.1:p.Tyr151Cys
NP_001121897.1:p.Tyr179Cys
NP_001121897.1:p.Tyr179Cys
NP_001280119.1:p.Tyr166Cys
NP_001280120.1:p.Tyr162Cys
NP_001280121.1:p.Tyr59Cys
NP_001280121.1:p.Tyr59Cys
NP_001280124.1:p.Tyr151Cys
NP_001280125.1:p.Tyr59Cys
NP_001337579.1:p.Tyr36Cys
NP_001337580.1:p.Tyr36Cys
NP_036354.1:p.Tyr176Cys
NP_036354.1:p.Tyr176Cys
LRG_220t1:c.536A>G
LRG_220:g.12668A>G
LRG_220p1:p.Tyr179Cys
NC_000001.10:g.45798475T>C
NM_001048171.1:c.494A>G
NM_001048174.1:c.452A>G
NM_001048174.2:c.452A>G
NM_001128425.1:c.536A>G
NM_001293192.1:c.176A>G
NM_012222.2:c.527A>G
NR_146882.2:n.680A>G
NR_146883.2:n.529A>G

Protein change:

Y151C; TYR165CYS

Links:

OMIM: 604933.0001; dbSNP: rs34612342

NCBI 1000 Genomes Browser:

rs34612342

Molecular consequence:

NM_001048171.2:c.452A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001048172.2:c.455A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001048173.2:c.452A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001048174.2:c.452A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001128425.2:c.536A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001293190.2:c.497A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001293191.2:c.485A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001293192.2:c.176A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001293195.2:c.452A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001293196.2:c.176A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001350650.2:c.107A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001350651.2:c.107A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_012222.3:c.527A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_146882.2:n.680A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146883.2:n.529A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000185514	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Feb 16, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16338133, 19032956, 19394335, 21063410, 23361220 Citation Link,
SCV000266097	University of Washington Department of Laboratory Medicine, University of Washington	criteria provided, single submitter (Shirts et al. (Genet Med 2016))	Pathogenic (Nov 20, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000537631	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 20, 2023)	germline	clinical testing	PubMed (20) [See all records that cite these PMIDs] 11818965, 12606733, 16338133, 16492921, 16557584, 17489848, 18534194, 19032956, 19394335, 19793053, 19953527, 20418187, 21063410, 21171015, 22266422, 23361220, 24444654, 27829682, 29147111, 25741868
SCV000788070	True Health Diagnostics	no assertion criteria provided	Pathogenic (Dec 8, 2017)	germline	clinical testing
SCV000821743	GeneKor MSA	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 1, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002532295	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Pathogenic (Mar 7, 2022)	germline	curation	PubMed (12) [See all records that cite these PMIDs] 19732775, 19032956, 23035301, 12606733, 16557584, 17489848, 19793053, 19836313, 20418187, 19394335, 21063410, 24444654 Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	3	not provided	not provided	3	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Improving performance of multigene panels for genomic analysis of cancer predisposition.

Shirts BH, Casadei S, Jacobson AL, Lee MK, Gulsuner S, Bennett RL, Miller M, Hall SA, Hampel H, Hisama FM, Naylor LV, Goetsch C, Leppig K, Tait JF, Scroggins SM, Turner EH, Livingston R, Salipante SJ, King MC, Walsh T, Pritchard CC.

Genet Med. 2016 Oct;18(10):974-81. doi: 10.1038/gim.2015.212. Epub 2016 Feb 4.

PubMed [citation]

PMID:: 26845104

Inherited variants of MYH associated with somatic G:C-->T:A mutations in colorectal tumors.

Al-Tassan N, Chmiel NH, Maynard J, Fleming N, Livingston AL, Williams GT, Hodges AK, Davies DR, David SS, Sampson JR, Cheadle JP.

Nat Genet. 2002 Feb;30(2):227-32. Epub 2002 Jan 30.

PubMed [citation]

PMID:: 11818965

See all PubMed Citations (24)

Details of each submission

From Ambry Genetics, SCV000185514.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The c.536A>G (p.Y179C) alteration is located in coding exon 7 of the MUTYH gene. This alteration results from a A to G substitution at nucleotide position 536, causing the tyrosine (Y) at amino acid position 179 to be replaced by a cysteine (C). Based on data from gnomAD, the G allele has an overall frequency of 0.154% (435/282806) total alleles studied. The highest observed frequency was 0.25% (323/129154) of European (non-Finnish) alleles. This alteration represents a founder mutation in multiple populations and accounts for a significant proportion of pathogenic MUTYH mutations reported to date (Nielsen, 2009; Aretz, 2014). A 2-fold increased risk of colorectal cancer (CRC) risk for carriers of a single (mono-allelic) MUTYH mutation has been reported as similar to the CRC risk of those with an affected first degree relative (Jones, 2009; Butterworth, 2006). A large scale meta-analysis to refine CRC risk estimates associated with MUTYH variants, including more than 20000 cases and 15000 controls, demonstrated an approximately 1.5 fold increase in CRC risk for carriers of the p.Y179C mutation (Theodoratou, 2010). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From University of Washington Department of Laboratory Medicine, University of Washington, SCV000266097.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)
2	not provided	1	not provided	not provided	clinical testing	PubMed (1)
3	not provided	1	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
2	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
3	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV000537631.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (20)

Description

This missense variant replaces tyrosine with cysteine at codon 179 of the MUTYH protein. This variant is also known as p.Tyr165Cys (c.494A>G) based on an alternate transcript, NM_001048171. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that the mutant protein is defective in DNA binding and repair, and glycosylase activity (PMID: 18534194, 19953527). This variant is a well-established pathogenic variant known to cause adenomatous polyposis and colorectal cancer in homozygous and compound heterozygous individuals (PMID: 11818965, 12606733, 16338133, 16492921, 16557584, 17489848, 18534194, 19032956, 19394335, 19793053, 20418187, 21063410, 21171015, 22266422, 23361220, 24444654, 27829682). This variant is one of two most common pathogenic MUTYH variants, which together account for up to 80% of MUTYH-associated disease observed in Caucasian individuals (PMID: 29147111). This variant has been identified in 435/282806 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From True Health Diagnostics, SCV000788070.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneKor MSA, SCV000821743.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This sequence change replaces tyrosine with cysteine at codon 179 of the MUTYH protein (p.Tyr179Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine (Grantham Score 194).This variant, also known as Y165C using an alternative reference sequence, has been published in the literature as one of the two common MUTYH missense mutations in Western populations, and, when found in combination with another pathogenic variant, is known to cause MUTYH-associated polyposis (MAP) (PMID: 19032956). It has been reported to co-segregate with disease in individuals affected with colorectal cancer, familial adenomatous polyposis (FAP), and attenuated FAP (PMID: 24444654; 21063410 ; 19793053 ; 17489848, 31159747) Experimental studies have shown that this variant disrupts MUTYH protein function (PMID: 20848659 ; 19953527 ; 11818965 ). The mutation database ClinVar contains entries for this variant (Variation ID:5293).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Sema4, Sema4, SCV002532295.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (12)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 19, 2024

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